Effects of antecedent prolonged exercise on subsequent counterregulatory responses to hypoglycemia

Galassetti, Pietro; Mann, Samuel; Tate, Donna B.; Neill, Ray A.; Costa, Fernando; Wasserman, David H.; Davis, Stephen N.

doi:10.1152/ajpendo.2001.280.6.e908

Cited by 96 publications

(111 citation statements)

References 44 publications

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“…Among the responses to subsequent hypoglycaemia, only the epinephrine response was reduced, and that by only about 30%, after exercise. Furthermore, the symptom responses to hypoglycaemia were not reduced in either study [35,37]. Thus, an additional factor, or factors, are likely to be involved in the mediation of HAAF.…”

Section: Pathophysiology Of Glucose Counterregulation In Type I Diabetesmentioning

confidence: 80%

Section: Pathophysiology Of Glucose Counterregulation In Type I Diabetesmentioning

confidence: 99%

“…It has been suggested that the cortisol response to antecedent hypoglycaemia mediates HAAF [34,35,36]. They found that antecedent cortisol infusion [34], and antecedent exercise (which releases cortisol) [35], mimics 6. Mean (±SE) total, neurogenic (autonomic) and neuroglycopenic symptoms scores during hyperinsulinaemic stepped hypoglycaemic clamps in patients with Type I diabetes studied the morning after clamped hyperglycaemia the previous day on one occasion (s) and after clamped hypoglycaemia the previous day on another occasion (s s).…”

Section: Pathophysiology Of Glucose Counterregulation In Type I Diabetesmentioning

confidence: 99%

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Hypoglycaemia: The limiting factor in the glycaemic management of Type I and Type II Diabetes*

2002

Diabetologia

727

574

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Hypoglycaemia is the limiting factor in the glycaemic management of diabetes. Iatrogenic hypoglycaemia is typically the result of the interplay of insulin excess and compromised glucose counterregulation in Type I (insulin-dependent) diabetes mellitus. Insulin concentrations do not decrease and glucagon and epinephrine concentrations do not increase normally as glucose concentrations decrease. The concept of hypoglycaemia-associated autonomic failure (HAAF) in Type I diabetes posits that recent antecedent iatrogenic hypoglycaemia causes both defective glucose counterregulation (by reducing the epinephrine response in the setting of an absent glucagon response) and hypoglycaemia unawareness (by reducing the autonomic and the resulting neurogenic symptom responses). Perhaps the most compelling support for HAAF is the finding that as little as 2 to 3 weeks of scrupulous avoidance of hypoglycaemia reverses hypoglycaemia unawareness and improves the reduced epinephrine component of defective glucose counterregulation in most affected patients. The mediator and mechanism of HAAF are not known but are under active investigation. The glucagon response to hypoglycaemia is also reduced in patients approaching the insulin deficient end of the spectrum of Type II (non-insulin-dependent) diabetes mellitus, and glycaemic thresholds for autonomic (including epinephrine) and symptomatic responses to hypoglycaemia are shifted to lower plasma glucose concentrations after hypoglycaemia in Type II diabetes. Thus, patients with advanced Type II diabetes are also at risk for HAAF. While it is possible to minimise the risk of hypoglycaemia by reducing risks -including a 2 to 3 week period of scrupulous avoidance of hypoglycaemia in patients with hypoglycaemia unawareness -methods that provide glucose-regulated insulin replacement or secretion are needed to eliminate hypoglycaemia and maintain euglycaemia over a lifetime of diabetes. [Diabetologia (2002) 45:937-948] Keywords Hypoglycaemia, glucagon, epinephrine, adrenal medulla, sympathetic nervous system, hypoglycaemia-associated autonomic failure.

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Section: Pathophysiology Of Glucose Counterregulation In Type I Diabetesmentioning

confidence: 80%

Section: Pathophysiology Of Glucose Counterregulation In Type I Diabetesmentioning

confidence: 99%

Section: Pathophysiology Of Glucose Counterregulation In Type I Diabetesmentioning

confidence: 99%

See 1 more Smart Citation

Hypoglycaemia: The limiting factor in the glycaemic management of Type I and Type II Diabetes*

2002

Diabetologia

727

574

View full text Add to dashboard Cite

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“…Thus, during endurance exercise, counterregulatory mechanisms similar to those of hypoglycaemia are activated to mobilise fuel. In healthy humans both antecedent exercise and antecedent hypoglycaemia attenuate symptoms and hormonal counterregulation during subsequent hypoglycaemia [7,8]. In elite endurance athletes, who like patients with Type 1 diabetes spend considerable time with limited fuel availability, performance capacity has been associated with the angiotensin-converting enzyme (ACE) genotype as the insertion (I) allele of the ACE gene that confers low ACE activity, compared to the deletion (D) allele [9], has been linked to superior performance capacity [10,11,12].…”

Section: Following the Diabetes Control And Complicationsmentioning

confidence: 99%

Prediction of Severe Hypoglycaemia by Angiotensin-Converting Enzyme Activity and Genotype in Type 1 Diabetes

et al. 2003

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Aims/hypothesis. We have previously shown a strong relationship between high angiotensin-converting enzyme (ACE) activity, presence of the deletion (D) allele of the ACE gene and recall of severe hypoglycaemic events in patients with Type 1 diabetes. This study was carried out to assess this relationship prospectively. Methods. We followed 171 adult outpatients with Type 1 diabetes in a one-year observational study with the recording of severe hypoglycaemia. Participants were characterised by serum ACE activity and ACE genotype and not treated with ACE inhibitors or angiotensin II receptor antagonists.Results. There was a positive relationship between serum ACE activity and rate of severe hypoglycaemia with a 2.7 times higher rate in the fourth quartile of ACE activity compared to the first quartile (p=0.0007). A similar relationship was observed for the subset of episodes with coma (2.9 times higher rate in fourth quartile compared to first quartile; p=0.048). The impact of serum ACE activity was most pronounced in C-peptide negative subjects (4.2 times higher rate in fourth quartile compared to first quartile; p=0.003), and in this subgroup carriers of the D allele of the ACE gene had higher rates of severe hypoglycaemia compared to the group homozygous for the insertion (I) allele. In a multiple regression analysis high serum ACE activity and impaired awareness of hypoglycaemia were identified as the only significant predictors of severe hypoglycemia. To avoid progression of these frequent episodes into severe hypoglycaemia patients rely on maintenance of performance capacity [3] until hypoglycaemic symptoms are recognised and self-treated or until the next pre-scheduled meal is ingested.Risk of severe hypoglycaemia is a major limiting factor for the achievement of good metabolic control [4] rendering prediction of individual risk of severe hypoglycaemia increasingly important. Loss of hypoglycaemic warning symptoms and blunted hormonal counterregulatory response are the most important known predictors of severe hypoglycaemia [4,5]. However, even patients at high risk according to these paFollowing the Diabetes Control and Complications Trial [1] a growing demand for strict glycaemic control has emerged to avoid late diabetic complications in Type 1 diabetes. As a consequence the majority of patients with Type 1 diabetes experience mild hypoglycaemia on a regular basis and recent studies applying continuous glucose monitoring indicate that pa-

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“…If cortisol is the mediator of HAAF, then any stimulus that releases cortisol, such as exercise, should reduce the responses to subsequent hypoglycemia. Indeed, two bouts (morning and afternoon) of relatively mild exercise (50% maximum oxygen consumption ϫ 90 min), compared with rest, has been reported to reduce the epinephrine, norepinephrine, muscle sympathetic nerve activity, pancreatic polypeptide, glucagon, and growth hormone responses-but not the symptomatic or cortisol responses-to hypoglycemia the next day (23).…”

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confidence: 99%

Limited Impact of Vigorous Exercise on Defenses Against Hypoglycemia

et al. 2002

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Hypoglycemia-associated autonomic failure (HAAF)-reduced autonomic (including adrenomedullary epinephrine) and symptomatic responses to hypoglycemia caused by recent antecedent hypoglycemia-plays a key role in the pathogenesis of defective glucose counterregulation and hypoglycemia unawareness and thus iatrogenic hypoglycemia in type 1 diabetes. On the basis of the findings that cortisol infusion mimics and deficient or inhibited cortisol secretion minimizes this phenomenon, it has been suggested that the cortisol response to antecedent hypoglycemia mediates HAAF. We tested the hypothesis that any stimulus that releases cortisol, such as exercise, reduces autonomic and symptomatic responses to subsequent hypoglycemia. Thirteen healthy young adults (four women) were studied on three occasions in random sequence: 1) cycle exercise (ϳ70% peak oxygen consumption) from 0830 to 0930 h and from 1200 to 1300 h on day 1 and hyperinsulinemic (2.0 mU ⅐ kg ؊1 ⅐ min ؊1 ) stepped hypoglycemic (85, 75, 65, 55, and 45 mg/dl) clamps on day 2, 2) rest on day 1 and identical hypoglycemic clamps on day 2, and 3) hyperinsulinemic-euglycemic clamps. Exercise raised plasma cortisol concentrations to 16.9 ؎ 1.9 (0930 h) and 16.6 ؎ 1.6 g/dl (1300 h) on day 1. Compared with rest on day 1, exercise on day 1 was associated with reduced epinephrine (P ‫؍‬ 0.0113) responses-but not norepinephrine (P ‫؍‬ 0.6270), neurogenic symptom (P ‫؍‬ 0.6470), pancreatic polypeptide (P ‫؍‬ 0.0629), or glucagon (P ‫؍‬ 0.0436, but higher) responses-to hypoglycemia on day 2. However, the effect was small. (The final day 2 hypoglycemia epinephrine values were 765 ؎ 106 pg/ml after rest on day 1 and 550 ؎ 94 pg/ml after exercise on day 1 compared with 30 ؎ 6 pg/ml during euglycemia.) These data are consistent with the hypothesis that the cortisol response to hypoglycemia mediates in part the reduced epinephrine response to subsequent hypoglycemia, one key component of HAAF in type 1 diabetes. However, the small effect suggests that an additional factor or factors may well be involved. These data do not support the hypothesis that the cortisol response to hypoglycemia mediates the reduced neurogenic symptom response to subsequent hypoglycemia, another key component of HAAF in type 1 diabetes. Diabetes 51:1485-1492, 2002 I atrogenic hypoglycemia is the limiting factor, both conceptually and in practice, in the glycemic management of diabetes (1-4). At least in type 1 diabetes, iatrogenic hypoglycemia is the result of the interplay of relative or absolute therapeutic insulin excess and compromised physiological and behavioral defenses against developing hypoglycemia (1,2,5-9). The concept of hypoglycemia-associated autonomic failure (HAAF) in type 1 diabetes (10 -16) posits that recent antecedent iatrogenic hypoglycemia, by reducing the autonomic (including the adrenomedullary epinephrine as well as the sympathetic neural norepinephrine and acetylcholine) responses and the resultant neurogenic symptomatic responses to a given level of subsequent hypoglycemia, cau...

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Effects of antecedent prolonged exercise on subsequent counterregulatory responses to hypoglycemia

Cited by 96 publications

References 44 publications

Hypoglycaemia: The limiting factor in the glycaemic management of Type I and Type II Diabetes*

Hypoglycaemia: The limiting factor in the glycaemic management of Type I and Type II Diabetes*

Prediction of Severe Hypoglycaemia by Angiotensin-Converting Enzyme Activity and Genotype in Type 1 Diabetes

Limited Impact of Vigorous Exercise on Defenses Against Hypoglycemia

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